External skin treatment agent composition containing prostacyclins as active ingredient

ABSTRACT

An external skin treatment agent composition containing an active ingredient comprising of a prostacyclin, and/or its optical isomer, having the formula (I): ##STR1## (wherein, R 1  is a hydrogen atom, a straight chain or branched alkyl group of C 1  to C 10 , or one equivalent of cations, R 2  is (CH 2 ) 2  R 21  or a substitutable C 3  to C 10  cycloalkyl group, where R 21  is a substitutable C 1  to C 10  straight chain or branched alkyl group or substitutable C 2  to C 10  straight chain or branched alkenyl group or alkynyl group, and R 3  and R 4  are independently a hydroxyl group or formula ##STR2## (wherein, R 5  is a C 1  to C 5  straight chain or branched alkyl group)) and a carrier.

TECHNICAL FIELD

The present invention relates to an external skin treatment agentcomposition. More specifically, it relates to an external skin treatmentagent composition containing a prostacyclin derivative as an activeingredient.

BACKGROUND ART

Prostaglandins are compounds which have diverse physiological actionssuch as a powerful action in suppressing blood platlet aggregation,action in reducing the vasodilation blood pressure, action insuppressing gastric acid secretion, smooth muscle contraction action,cell protection action, and diuretic action and is useful for thetreatment or prevention of myocardial infarct, cardiac angina,arteriosclerosis, hypertension, duodenal ulcers, induced parturition,abortion, etc.

On the other hand, in recent years, there has been a tendency toward anincrease of skin ulcers, in particular, the decubitus ulcers knowncommonly as bedsores, along with the higher age of the subjects beingtreated for various ailments. For example, about 5% of the approximately12 million senior citizens in Japan today, or 600,000 people, arebed-ridden. These people are said to suffer from decubitus ulcers at ahigh frequency. In the past, the treatment for skin ulcers, includingdecubitus ulcers, consisted of improvement of local conditions usingantibiotics, antibacterial agents, ointments containing enzymes etc.,skin cleaning solutions, or water absorbing polymer powders, woundcovering agents, etc. These have been tried along with removal andmitigation of the pressure on the diseased sites, surgical debridementfor removal of the destroyed tissue, treatment of systemic conditions bytransfusions, intraintestinal nutrition, and IVH, but these treatmentsstill cannot be said to be sufficiently effective. On the other hand,attempts have been made to apply prostaglandin E, prostaglandin F, andprostaglandin I₁ transdermal preparations to skin ulcers, includingdecubitus ulcers, for the purpose of improvement of skin ulcers byapplication to local areas, but the stability of the main medication,the release of the main medication from the ointment, the stimulus tothe skin, and the efficacy have not always necessarily met clinicalrequirements.

Natural prostacyclin, however, is a local hormone produced mainly by thehemangioendothelium in the body. Attempts have been made to make use ofits powerful physiological activity, for example, its activity insuppressing aggregation of blood platlets, its vasodilation activity,etc. to use the same as a direct pharmaceutical (P. J. Lewis, J. O.Grady, Clinical Pharmacology of Prostaglandin). Natural prostacyclin,however, contains an enol-ether bond which is extremely easilyhydrolyzed in the molecules, and therefore, easily loses its activityunder neutral or acidic conditions. Accordingly, it cannot be said to bea desirable compound as a pharmaceutical due to its chemicalinstability. Therefore, intensive research has been carried out onsynthesizing a synthetic prostacyclin which has a similar physiologicalactivity as natural prostacyclin and is chemically stable (Synthesis,1984, 449). The present inventors succeeded in synthesizing theprostacyclin analogs, which are 9(O)-methano-Δ⁶(9α) -prostaglandins I₂(isocarbacyclin), derivatives which are sufficiently satisfactory in thechemical stability, by replacing oxygen atoms at the 6(9α)-position ofprostacyclin with the methine group (--CH═) (see Japanese UnexaminedPatent Publication (Kokai) No. 59-210044). This derivative hasphysiological activity, such as a powerful action in inhibitory effecton aggregation of blood platlets and an action in reducing the bloodpressure, comparable with natural prostacyclin and is useful forcardiovascular system (see Japanese Unexamined Patent Publication(Kokai) Nos. 59-210044 and 61-197518).

DISCLOSURE OF THE INVENTION

The present inventors took note of the powerful activity in suppressingaggregation of blood platlets and vasodilation action of stabilizedprostacyclin derivatives (isocarbacyclins) and engaged in intensivestudies on the possibilities of it as an external skin treatment agentsuch as an agent for treatment of skin ulcers, including decubitusulcers, and as a result, found activity suggesting that possibility inisocarbacyclin in the present invention and thereby reached the presentinvention.

That is, in accordance with the present invention, there is provided anexternal skin treatment agent composition containing an activeingredient comprising a prostacyclin, and/or its optical isomer, havingthe formula (I): ##STR3## (wherein, R¹ is a hydrogen atom, a straightchain or branched alkyl group of C₁ to C₁₀, or one equivalent of acation, R² is (CH₂)₂ R²¹ or a substitutable C₃ to C₁₀ cycloalkyl group,where R²¹ is a substitutable C₁ to C₁₀ straight chain or branched alkylgroup or substitutable C₂ to C₁₀ straight chain or branched alkenylgroup or alkinyl group, and R³ and R⁴ are independently a hydroxyl groupor formula: ##STR4## (wherein, R⁵ is a C₁ to C₅ straight chain orbranched alkyl group)) and a carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the effect of increasing the flow of blood at theskin by to the external skin treatment composition agent composition ofthe present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

In formula (I), R¹ is a hydrogen atom, a C₁ to C₁₀ straight chain orbranched alkyl group, or one equivalent weight of cations. As the C₁ toC₁₀ alkyl group, mention may be made, for example, of a methyl group,ethyl group, n-propyl group, iso-propyl group, n-butyl group, sec-butylgroup, tert-butyl group, n-pentyl group, n-hexyl group, n-heptyl group,n-octyl group, n-nonyl group, n-decyl group, etc. Among these, a C₁ toC₆ alkyl group, in particular, a C₁ to C₄ alkyl group, is preferable. Asthe one equivalent weight of cations, mention may be made for example ofalkali metal cations such as Na⁺, K⁺ ; bivalent or trivalent metalcations such as 1/2Ca²⁺, 1/2Mg²⁺, 1/3Al³⁺ ; and ammonium cations such asammonium ions, tetramethyl ammonium ions. As R¹, a hydrogen atom ormethyl group are particularly preferred, more particularly a methylgroup is preferred.

In formula (I), R² is (CH₂)₂ R²¹ or a substitutable C₃ to C₁₀ cycloalkylgroup. Here, R²¹ is a substitutable C₁ to C₁₀ straight chain or branchedalkyl group or substitutable C₂ to C₁₀ straight chain or branchedalkenyl group or alkinyl group. As the unsubstituted C₁ to C₁₀ alkylgroup related to R₂₁, mention may be made for example of a methyl group,ethyl group, n-propyl group, iso-propyl group, n-butyl group, sec-butylgroup, tert-butyl group, n-pentyl group, 2-methylbutyl-4-yl group,3-methylbutyl-4-yl group, 4-methylbutyl-4-yl group, n-hexyl group,2-methylpentyl-5-yl group, 3-methylpentyl-5-yl group,4-methylpentyl-5-yl group, 5-methylpentyl-5-yl group, n-heptyl group,2-methylhexyl-6-yl group, 3-methylhexyl-6-yl group, 4-methylhexyl-6-ylgroup, 5-methylhexyl-6-yl group, 6-methylhexyl-6-yl group, etc. Amongthese, a C₁ to C₈ alkyl group, in particular a C₅ to C₈ alkyl group, ispreferred.

Further, as the unsubstituted C₂ to C₁₀ alkenyl group relating to R²¹,mention may be made for example of a 1-methylvinyl group, vinyl group,1-propenyl group, 1-butenyl group, 1-pentenyl group, 1-hexenyl group,1-heptenyl group, allyl group, methallyl group, 2-butenyl group,2-pentenyl group, 2-hexenyl group, 2-heptenyl group, 1-pentene-2-ylgroup, 3-methyl-1-butene-1-yl group, 3-methyl-1-pentene-1-yl group,4-methyl-1-pentene-1-yl group, 3-methyl-1-hexene-1-yl group,4-methyl-1-hexene-1-yl group, 3-methyl-1-heptene-1-yl group,5-methyl-1-heptene-1-yl group, 3,3-dimethyl-1-heptene-1-yl group,2-pentene-3-yl group, 3-methyl-2-butenyl group, 4-methyl-2-pentenylgroup, 4-methyl-2-hexenyl group, 5-methyl-2-heptenyl group,4,4-dimethyl-2-hexenyl group, 1-butene-4-yl group,2-methyl-1-butene-4-yl group, 3-methyl-1-butene-4-yl group,2-pentene-4-yl group, 3-hexenyl group, 3-heptenyl group,3,3-dimethyl-1-butene-4-yl group, 1-pentene-5-yl group,4-methyl-pentene-5-yl group, 4,4-dimethyl-pentene-5-yl group,3-methyl-pentene-5-yl group, 2-methyl-pentene-5-yl group, 2-hexene-6-ylgroup, 2-methyl-2-hexene-6-yl group, 5-methyl-2-hexene-6-yl group,5,5-dimethyl-2-hexene-6-yl group, 4-ethyl-3-hexenyl group,4-methyl-3-hexenyl group, 2-methyl-2-pentene group, 2-methyl-3-hexenylgroup, 5-methyl-3-hexenyl group, 2-methyl-3-heptenyl group,6-methyl-3-heptenyl group, 2,5-dimethyl-2-hexene-6-yl group,2-methyl-2-heptene-6-yl group, 2,6-dimethyl-2-heptene-6-yl group,3-heptene-7-yl group, 3-methyl-heptene-7-yl group, 3-ethyl-heptene-7-ylgroup, 5-methyl-heptene-7-yl group, 6-methyl-heptene-7-yl group,6,6-dimethyl-heptene-7-yl group, etc. Among these, a C₂ to C₈ alkenylgroup, in particular a C₅ to C₈ alkenyl group, is preferable.

Further, as the unsubstituted C₂ to C₁₀ alkynyl group relating to theR²¹, mention may be made for example of an ethynyl group, 1-propine-3-ylgroup, butynyl group, pentynyl group, hexynyl group, heptynyl group,3-methyl-butynyl group, 3,3-dimethyl-butynyl group, 3-methyl-pentynylgroup, 3,3-dimethyl-pentynyl group, 3-ethyl-pentynyl group,4-methyl-pentynyl group, 4,4-dimethyl-pentynyl group, 3-methyl-hexynylgroup, 3,3-dimethyl-hexynyl group, 5-methyl-hexnyl group,5,5-dimethyl-hexynyl group, 3-methyl-heptynyl group,3,3-dimethyl-heptynyl group, 5-methyl-heptynyl group, 5-ethyl-heptynylgroup, 5,5-dimethyl-heptynyl group, 1-propine-3-yl group, 1-butine-3-ylgroup, 2-pentine-3-yl group, 2-butine-1-yl group, 2-pentine-1-yl group,4-methyl-2-pentine-1-yl group, 4,4-dimethyl-2-pentine-1-yl group,2-hexine-1-yl group, 4-methyl-2-hexine-1-yl group, 4-ethyl-2-hexine-1-ylgroup, 4,4-dimethyl-2-hexine-1-yl group, 2-heptine-1-yl group,3-octine-2-yl group, 4-methyl-2 -heptine-1-yl group,4,4-dimethyl-2-heptine-1-yl group, 5,5-dimethyl-2-heptine-1-yl group,5-ethyl-2-heptine-1-yl group, 3-heptine-2-yl group, 1-butine-4-yl group,1-pentine-4-yl group, 3-methyl-1-butine-4-yl group, 2-pentine-5-ylgroup, 3-hexine-1-yl group, 5-methyl-3-hexine-1-yl group,2-methyl-3-hexine-1-yl group, 5,5-dimethyl-3-hexine-1-yl group,2,2-dimethyl-3-hexine-1-yl group, 3-heptine-1-yl group, 4-octine-2-ylgroup, 2-methyl-4-octine-2-yl group, 2,2-dimethyl-3-heptine-1-yl group,2-methyl-3-heptine-1-yl group, 5-methyl-3-heptine-1-yl group,2-hexine-5-yl group, 5-ethyl-3-heptine-1-yl group,6-methyl-3-heptine-1-yl group, 6,6-dimethyl-3-heptine-1-yl group,1-pentine-5-yl group, 1-hexine-5-yl group, 4-methyl-1-pentine-5-ylgroup, 4,4-dimethyl-1-pentine-5-yl group, 3-methyl-1-pentine-5-yl group,3,3-dimethyl-1-pentine-5-yl group, 2-hexine-6-yl group, 2-heptine-6-ylgroup, 5-methyl-2-hexine-6-yl group, 5,5-dimethyl-2-hexine-6-yl group,4-methyl-2-hexine-6-yl group, 4,4-dimethyl-2-hexine-6-yl group,3-heptine-7-yl group, 3-octine-7-yl group, 6-methyl-3-heptine-7-ylgroup, 6,6-dimethyl-3-heptine-7-yl group, 5-methyl-3-heptine-7-yl group,2-methyl-3-heptine-7-yl group, 2,2-dimethyl-3-heptine-7-yl group,1-hexine-6-yl group, 1-heptine-6-yl group, 6-methyl-1-heptine-6-ylgroup, 5-methyl-1-hexine-6-yl group, 5,5-dimethyl-1-hexine-6-yl group,4-methyl-1-hexine-6-yl group, 3-methyl-1-hexine-6-yl group,3,3-dimethyl-1-hexine-6-yl group, 2-heptine-7-yl group, 2-octine-7-ylgroup, 7-methyl-2-octine-7-yl group, 5,5-dimethyl-2-heptine-7-yl group,4-methyl-2-heptine-7-yl group, 4,4-dimethyl-2-heptine-7-yl group,1-heptine-7 -yl group, 1-octine-7-yl group, 7-methyl-1-octine-7-ylgroup, 5-methyl-1-heptine-7-yl group, 4-methyl-1-heptine-7-yl group,3-methyl-1-heptine-7-yl group, 3,3-dimethyl-1-heptine-7-yl group,4,4-dimethyl-1-heptine-7-yl group, etc. Among these, a C₂ to C₈ alkenylgroup, in particular a C₅ to C₈ alkenyl group, is preferred.

As the R²¹ substituent groups, mention may be made of halogen atoms suchas fluorine, chlorine, lower alkoxy groups such as, a methoxy group,ethoxy group, propoxy group, butoxy group, such as cyclopentyl group,cyclohexyl group, C₃ to C₈ cycloalkyl groups. Among these, a loweralkoxy group or cycloalkyl group is preferred.

In the --CH₂)₂ R²¹ relating to R² in the formula (I), R²¹ is preferablya C₁ to C₅ straight chain or branched alkyl group. As the C₁ to C₅ alkylgroup, mention may be made for example of a methyl group, ethyl group,n-propyl group, iso-propyl group, n-butyl group, sec-butyl group,tert-butyl group, n-hexyl group, etc. Among these, as the R²¹, a C₃ toC₅ alkyl group is preferred, more preferably an n-propyl group orn-butyl group, particularly preferably an n-propyl group.

As specific examples of the cycloalkyl group in the case where the R²relating to formula (I) is a substitutable C₃ to C₁₀ cycloalkyl group,mention may be made of a cyclopentyl group, a cyclohexyl group, etc. Inparticular, a C₃ to C₈ cycloalkyl group, in particular a C₄ to C₇cycloalkyl group, is preferable. It should be noted that as thesubstituent group, mention may be made, for example, of C₁ to C₆ loweralkyl group such as a methyl group, ethyl group, propyl group, hexylgroup, a halogen atom such as a fluorine, chlorine, lower alkoxylgroups, such as a methoxy group, ethoxy group, propoxy group, butoxygroup, halogenated lower alkyl group, such as a trifluoromethyl group.

As the R² in formula (I), mention may be made of --CH₂)₂ R²¹ as apreferable example.

In formula (I), R³ and R⁴ are independently, that is, the same ordifferently, a hydroxyl group or the formula: ##STR5## Here, R⁵ is a C₁to C₅ straight chain or branched alkyl group, for example, mention maybe made of those similar to the examples of R². As the R⁵, a C₁ to C₃alkyl group is preferable, in particular a straight chain one. It shouldbe noted that as R⁵, a methyl group is particularly preferred. Further,as the R³ and R⁴, a hydroxyl group is particularly preferable.

The prostacyclins expressed in formula (I) with configurations of the8-, 9-, 11-, 12-, and 15-positions the same as natural prostacyclins area particularly useful sterioisomer, but the present invention includesthe stereoisomers resulting from different configurations thereof andany combinations thereof.

Preferable specific examples of the prostacyclin usable in the presentinvention are as follows:

(1) 9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(2) 20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(3) 19,20-dinol-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(4) 20-nol-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(5) 19 -methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(6) 18-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(7) 20-ethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(8) 20-isopropyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(9) 20-methyl-20-ethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(10) 19-methyl-20-ethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(11) 18-methyl-20-ethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(12) 20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(13) 22-methyl-20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(14) 21-methyl-20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(15) 20-methyl-20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(16) 19-methyl-20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(17) 18-methyl-20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(18) 20-nol-18-methylene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(19) 20-nol-18,19-dehydro-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(20) 18,19-dehydro-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(21) 18,19-dehydro-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(22) 18,19-dehydro-20-ethyl-9(O)-methano-Δ⁶(9α) -prostaglandin-I₁

(23) 18,19-dehydro-20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(24) 18,19-dehydro-20-butyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(25) 18-methylene-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(26) 18,19-dehydro-20,20-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(27) 18,19-dehydro-20-methyl-20-ethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(28) 18,19-dehydro-20-isopropyl-20-ethyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(29) 18,19-dehydro-20-methyl-20-butyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(30) 18,19-dehydro-20-(1-methylpropyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(31) 18,19-dehydro-20-methyl-20-propyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(32) 18,19-dehydro-20,20-dimethyl-20-butyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(33) 19,20-dehydro-9(O) -methano-Δ⁶(9α) -prostaglandin I₁

(34) 19,20-dehydro-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(35) 19,20-dehydro-19-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(36) 19,20-dehydro-20-ethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(37) 19,20-dehydro-20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(38) 19,20-dehydro-20-butyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(39) 19,20-dehydro-18,20-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(40) 19,20-dehydro-20-(1-methylpropyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(41) 19,20-dehydro-20-isopropyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(42) 19,20-dehydro-20-(2-methylbutyl)-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(43) 19,20-dehydro-20-(1,1-dimethylpropyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(44) 20-methylene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(45) 20-methyl-20-methylene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(46) 19-methyl-20-methylene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(47) 20-ethylidene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(48) 20-propylidene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(49) 20-butylidene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(50) 20-(1-ethylbutylidene)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(51) 20-(1-methylbutylidene)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(52) 20-(1-methylethylidene)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(53) 19-methyl-20-propylidene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(54) 20-(2-methylpropylidene)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(55) 19-methyl-20-butylidene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(56) 20-(3-methylbutylidene)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(57) 19 19-dimethyl-20-methylene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(58) 20-vinyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(59) 19-methyl-20-vinyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(60) 19,19-dimethyl-20-vinyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(61) 20-methyl-20-vinyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(62) 20-(1-methylvinyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(63) 20-(1-propenyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(64) 20-(2-methyl-1-propenyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(65) 19-methyl-20-(1-propenyl )-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(66) 19,19-dimethyl-20-(1-propenyl)-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(67) 19-methyl-20-(2-methyl-1-propenyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(68) 18-methyl-20-(2-methyl-1-propenyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(69) 18,18-dimethyl-20-(2-methyl-1-propenyl)-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(70) 20-(1-butenyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(71) 20-(2-methyl-1-butenyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(72) 20-(2-ethyl-1-butenyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(73) 20-methyl-20-butenyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(74) 19-methyl-20-butenyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(75) 19,19-dimethyl-20-butenyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(76) 20-nol-18,19-tetrahydro-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(77) 18,19-tetrahydro-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(78) 18,19-tetrahydro-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(79) 18,19-tetrahydro-20-ethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(80) 18,19-tetrahydro-20-butyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(81) 18,19-tetrahydro-20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(82) 18,19-tetrahydro-20,20-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(83) 18,19-tetrahydro-20,20,20-trimethyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(84) 18,19-tetrahydro-20-methyl-20-ethyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(85) 18,19-tetrahydro-20,20-dimethyl-20-ethyl-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(86) 18,19-tetrahydro-20,20-diethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(87) 18,19-tetrahydro-20-isopropyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(88) 18,19-tetrahydro-20-t-butyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(89) 18,19-tetrahydro-20-methyl-20-propyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(90) 18,19-tetrahydro-20,20-dimethyl-20-propyl-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(91) 18,19-tetrahydro-20-(2-methylpropyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(92) 18,19-tetrahydro-20-(2,2-dimethylpropyl)-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(93) 18,19-tetrahydro-20-methyl-20-butyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(94) 18,19-tetrahydro-20,20-dimethyl-20-butyl-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(95) 18,19-tetrahydro-20-(2-methylbutyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(96) 18,19-tetrahydro-20-(2-ethylbutyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(97) 18,19-tetrahydro-20-(2,2-dimethylbutyl)-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(98) 19,20-tetrahydro-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(99) 19,20-tetrahydro-18-methyl-9(O)-methano-Δ⁹(6α) -prostaglandin I₁

(100) 19,20-tetrahydro-18,20-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(101) 19,20-tetrahydro-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(102) 19,20-tetrahydro-20-ethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(103) 19,20-tetrahydro-20-isopropyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(104) 19,20-tetrahydro-20-t-butyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(105) 19,20-tetrahydro-20-propyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(106) 19,20-tetrahydro-20-(1-methylpropyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(107) 19,20-tetrahydro-20-(1-ethylpropyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(108) 19,20-tetrahydro-20-(1,1-dimethylpropyl)-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(109) 19,20-tetrahydro-20-butyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(110) 19,20-tetrahydro-18-dimethyl-20-butyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(111) 19,20-tetrahydro-20-(1-methylbutyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(112) 19,20-tetrahydro-20-(1,1-dimethylbutyl)-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(113) 19,20-tetrahydro-20-(2,2-dimethylbutyl)-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(114) 19,20-tetrahydro-20-(2-ethylbutyl)-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(115) 19,20-tetrahydro-18-methyl-20-propyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(116) 20-methylidene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(117) 20-methylidene-18-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(118) 20-methylidene-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(119) 20-ethylidene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(120) 20-propylidene-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(121) 20-(2-methylpropylidine)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(122) 20-propylidine-19-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(123) 20-(2,2-dimethylpropylidine)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(124) 20-propylidine-19,19-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(125) 20-butylidine-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(126) 20-butylidine-18-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(127) 20-butylidine-18,18-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(128) 20-butylidine-18,18-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(129) 20-butylidine-19,19-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(130) 20-butylidine-19-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(131) 20-(2-methylbutylidine)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(132) 20-(2-ethylbutylidine)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(133) 20-(3-methylbutylidine)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(134) 20-(3,3-dimethylbutylidine)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(135) 20-(3,3-dimethylbutylidine)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(136) 20-ethynyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(137) 20-ethynyl-18-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(138) 20-ethynyl-19-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(139) 20-ethynyl-19,19-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(140) 20-ethynyl-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(141) 20-ethynyl-20,20-trimethyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(142) 20-(1-propynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(143) 20-(1-propynyl)-18-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(144) 20-(1-propynyl)-19-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(145) 20-(1-propynyl)-19,19-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(146) 20-(1-propynyl)-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(147) 20-(1-propynyl)-20,20-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(148) 20-(1-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(149) 20-(1-butynyl)-18-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(150) 20-(1-butynyl)-19-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(151) 20-(1-butynyl)-19,19-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(152) 20-(1-butynyl)-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(153) 20-(3-methyl-1-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(154) 20-(3,3-dimethyl-1-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(155) 20-(2-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(156) 20-(2-propynyl)-18-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(157) 20-(2-propynyl)-18,18-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(158) 20-(2-propynyl)-19-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(159) 20-(2-propynyl)-19,19-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(160) 20-(2-propynyl)-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(161) 20-(1-methyl-2-propynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(162) 20-(1,1-dimethyl-2-propynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(163) 20-(2-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(164) 20-(2-butynyl)-18-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(165) 20-(2-butynyl)-18,18-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(166) 20-(2-butynyl)-19,19-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(167) 20-(2-butynyl)-20,20-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(168) 20-(1-methyl-2-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(169) 20-(1,1-dimethyl-2-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(170) 20-(3-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(171) 20-(3-butynyl)-18-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(172) 20-(3-butynyl)-18,18-dimethyl-9(O)-methano-Δ⁶(9α) -prostaglandinI₁

(173) 20-(3-butynyl)-20-methyl-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(174) 20-(1-methyl-3-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(175) 20-(2-methyl-3-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(176) 20-(2,2-dimethyl-3-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(177) 20-(1,1-dimethyl-3-butynyl)-9(O)-methano-Δ⁶(9α) -prostaglandin I₁

(178) 16,17,18,19,20-pentanol-15-cyclopentyl-9(O)-methano-Δ⁶(9α)-prostaglandin I₁

(179) 16,17,18,19,20-pentanol-15-cyclohexyl-9(O) -methano-Δ⁶(9α)-prostaglandin I₁

(180)16,17,18,19,20-pentanol-15-(2-chlorohexyl-9(O)-methano-Δ⁶(9.alpha.)-prostaglandin I₁

(181)16,17,18,19,20-pentanol-15-(3-trifluoromethylcyclohexyl)-9(O)-methano-.DELTA.⁶(9α)-prostaglandin I₁

(182) 17-ethoxy-9-(O) -methano-Δ⁶(9α) -prostaglandin I₁

(183) An ethyl ester of (1) to (182)

(184) A butyl ester of (1) to (182)

(185) A sodium salt of (1) to (182)

(186) A potassium salt of (1) to (182)

(187) An ammonium salt of (1) to (182)

but the invention is not limited to the same.

The prostacyclin of the above formula (I) is easily produced by knownmethods. These processes of production are described in, for example,Japanese Unexamined Patent Publication (Kokai) Nos. 59-210044,61-197518, etc.

It became clear that there was a powerful skin ulcer treatment activityupon use of the prostacyclin of the formula (I) as an external skintreatment agent composition, in particular, a transdermal agent. Forexample, application of an ointment containing prostacyclin of formula(I) to a diseased location, that is, a skin ulcer (rabbit decubitusulcer lesion model) prepared by applying pressure to the skin on theback of a rabbit, exhibited a therapeutic effect. Further, the amount ofthe blood flow of the skin containing the prostacyclin of formula (I)was remarkably increased.

The above active compound may be used as an external skin treatmentagent, in particular, an agent for treatment of skin ulcers, forexample, decubitus ulcers, scald ulcers, angiopathic ulcers, diabeticulcers, peripheral circulatory disorders, ulcers accompanying collagendiseases, and other ulcers.

As the preparation of the transdermal agent composition having as anactive ingredient the prostacyclin of the formula (I), mention may bemade of an ointment, cream, lotion, liquid, etc.

The concentration of the active ingredient in the external skintreatment agent composition according to the present invention is notparticularly limited, but preferably is 10⁻⁶ to 10⁻¹ % by weight, morepreferably 10⁻⁵ to 10⁻² % by weight, in terms of the total composition.

As the carrier (base) of the external skin treatment agent of thepresent invention, mention may be made, for example, of castor oil,olive oil, sesame oil, safflower oil, and other fatty oils, lanolin,white, yellow, or hydrophilic vaselin, beeswax, bleached beeswax,spermaceti wax, paraffin wax, and other waxes, oleyl alcohol, isostearylalcohol, octyl dodeca alcohol, hexyl decanol, and other higher alcohols,glycerin, diglycerin, ethylene glycerol, propylene glycol, sorbitol,1,3-butanediol, and other glycols. Further, as the solubilizing agent ofthe prostacyclin, use may be made of ethanol, dimethylsulfoxide,polyethylene glycol, etc. Also, in accordance with need, use may also bemade of antioxidants such as paraoxyl benzoic acid esters, sodiumbenzoate, salicylic acid, sorbic acid, boric acid, and otherpreservatives, dibutylhydroxytoluene, and the like. In addition,suitable amounts of oil components, surfactants, water, moistureretainers, thickeners, fragrances, dyes, etc. may be added to an extentnot impairing the effect of the present invention.

To promote the transdermal absorption of prostacyclin, an absorptionpromotor such as diisopropyl adipate, diethyl sebacate, ethyl caproate,ethyl laurate, etc. may be added.

An ointment may be produced by an ordinary method. For example, mentionmay be made of the method of adding a fatty oil to a prostacyclin,dissolving the same in it, adding this solution to a separately warmedand melted wax, homogeneously mixing them, and then cooling. A cream canbe produced by an ordinary method. For example, mention may be made ofthe method of heating and melting a prostacyclin and an oil phasecomponent (fatty oil, surfactant), adding heated water to this, adding amixture of glycols, while stirring, and then cooling.

Aside from these preparations, mention may be made of preparations suchas lotions, liquids, pastes, cataplasms and aerosols. The preparationsmay be produced by ordinary methods.

The dosage of the prostacyclin differs depending on the type of thecompound, the state of the disease, etc., but the medication is usuallyadministered in an amount of from about 1 ng to about 1 mg/site.Accordingly, the amount of the prostacyclin contained in the transdermalmedication is determined by the dosage.

The transdermal medication having a prostacyclin as an active ingredientaccording to the present invention, as mentioned earlier, is appliedlocally to the skin, so is limited in location of action and thereforecan exhibit a pharmacological activity just at a specific site.

According to the present invention, it is clear that prostaglandin ofthe formula (I) exhibits a therapeutic effect on skin ulcers. Note thatthe external skin ointment of the present invention was not observed toparticularly have acute toxicity.

EXAMPLES

The present invention will be explained in further detail by Examples.

EXAMPLE 1

One hundred grams of an ointment having the following composition wereprepared.

    ______________________________________                                        9(O)-methano-Δ.sup.6(9α) -prostaglandin I.sub.1                                            0.05   mg                                            Beeswax                  33     g                                             Vegetable oil            77     g                                             ______________________________________                                    

EXAMPLE 2

One hundred grams of a cream having the following composition wereprepared.

    ______________________________________                                        9(O)-methano-Δ.sup.6(9α) -prostaglandin I.sub.1                                             0.05   mg                                           Beeswax                   10     g                                            Paraffin wax              6      g                                            Lanolin                   3      g                                            Isopropyl myristate       6      g                                            Squalane                  8      g                                            Liquid paraffin           25     g                                            Sorbitan monostearate     4      g                                            Polyoxyethylenesorbitan monostearate                                                                    2      g                                            Preservative              q.s.                                                Propylene glycol          2      g                                            Water                     30     g                                            ______________________________________                                    

EXAMPLE 3

Transdermal therapeutic effect on skin ulcers by 9(O)-methano-Δ⁶(9α)-prostaglandin I₁

Coating an ointment containing 9(O)-methano-Δ⁶(9α) -prostaglandin I₁ toa skin ulcer (rabbit decubitus ulcer lesion model) prepared by applyingpressure to the skin on the back of a rabbit exhibited a therapeuticeffect. That is, the skin areas on the III trochanters on the left andright of Japanese white male rabbits fasted for 15 to 20 days weredipilated and pressure was applied on those portions to prepare skinulcers. Subsequently, an ointment containing prostacyclin was coated onthe right lesions of the subjects and vaseline on the left lesions oncea day in amounts of 0.02 g/site. The curing process of the lesions wasfound by the ratio of area by the following equation in accordance withthe method of Fukawa (Applied Pharmacology, 7, 1305, 1973).

Ratio of area (%)=(long length×short length of ulcer area) (dayobserved)/(long length×short length of ulcer area) (day ulcerprepared)×100.

The results are shown in Table 1. The lesions coated with the ointmentcontaining the prostacyclin of the formula (I) shrank significantlycompared with the control sites on day 3, 5, and 7 and a therapeuticeffect was confirmed.

                                      TABLE 1                                     __________________________________________________________________________             Ratio of area of wound (%)                                           Concentration                                                                          0    3      5      7       10 (days)                                 __________________________________________________________________________    0.032 μg/g                                                                       R.sup.a)                                                                         100  62.31 ± 5.82                                                                      38.51 ± 5.98                                                                      16.41 ± 2.22                                                                       8.00 ± 1.90                                     (N = 11)                                                                           (N = 11)                                                                             (N = 11)                                                                             (N = 11)                                                                              (N = 11)                                        L.sup.b)                                                                         100  72.43 ± 6.37                                                                      41.02 ± 7.04                                                                      20.45 ± 3.27                                                                       8.85 ± 2.26                            0.16 μg/g                                                                        R.sup.a)                                                                         100  62.52 ± 6.69                                                                      37.86 ± 6.57                                                                      20.45 ± 4.78*                                                                      15.18 ± 6.85                                    (N = 11)                                                                           (N = 11)                                                                             (N = 11)                                                                             (N = 11)                                                                              (N = 11)                                        L.sup.b)                                                                         100  83.28 ± 7.87                                                                      59.18 ± 8.74                                                                      35.58 ± 4.39                                                                       24.27 ± 3.23                           0.8 μg/g                                                                         R.sup.a)                                                                         100  60.70 ± 6.15*                                                                     35.24 ± 6.18*                                                                     18.02 ± 3.56**                                                                     8.31 ± 2.01                                     (N = 11)                                                                           (N = 11)                                                                             (N = 11)                                                                             (N = 11)                                                                              (N = 11)                                        L.sup.b)                                                                         100  82.16 ± 4.61                                                                      54.35 ± 5.26                                                                      35.79 ± 3.88                                                                       16.41 ± 4.08                           __________________________________________________________________________     Figures of ratio of area of wound are mean values ± standard error.        N: Number of animals used                                                     .sup.a) Right side: specimen applied                                          .sup.b) Left side (control): vaseline applied                                 *5% significance in comparison with left side (control)                       **1% significance in comparison with left side (control)                 

EXAMPLE 4

Transdermal action of increasing amount of blood flow of skin by9(O)-methano-Δ⁶(9α) -prostaglandin I₁

An ointment containing 9(O)-methano-Δ⁶(9α) -prostaglandin I₁ remarkablyincreased the amount of the blood flow of the skin at the sites ofadministration of hairless rats as shown in FIG. 1.

The external skin treatment agent composition having the prostacyclin offormula (I) of the present invention as its active ingredient exhibiteda superior therapeutic effect.

We claim:
 1. An external skin ulcer treatment agent compositioncontaining an active ingredient comprising a prostacyclin, and/or itsoptical isomer, having the formula (I): ##STR6## (wherein, R¹ is ahydrogen atom, a straight chain or branched alkyl group of C₁ to C₁₀, orone equivalent of cations, R² is (CH₂)₂ R²¹ or a substitutable C₃ to C₁₀cycloalkyl group, where R²¹ is a substitutable C₁ to C₁₀ straight chainor branched alkyl group or substitutable C₂ to C₁₀ straight chain orbranched alkenyl group or alkynyl group, and R³ and R⁴ are independentlya hydroxyl group or formula: ##STR7## (wherein, R⁵ is a C₁ to C₅straight chain or branched alkyl group)) and a carrier.
 2. An externalskin ulcer treatment agent composition as claimed in claim 1, whereinthe R¹ in formula (I) is a hydrogen atom or a methyl group.
 3. Theexternal skin ulcer treatment agent composition claimed in claim 1,wherein R¹ in formula (I) is a hydrogen atom or a methyl group, and R²in formula (I) is a pentyl group.
 4. The external skin ulcer treatmentagent composition claimed in claim 1, wherein R² in formula (I) is apentyl group.
 5. The external skin ulcer treatment agent compositionclaimed in claim 1, wherein the external skin treatment agent in formula(I) is a transdermal agent.
 6. The external skin ulcer treatment agentcomposition claimed in claim 1, wherein R¹ in formula (I) is a hydrogenatom or a methyl group, and the external skin treatment agent in formula(I) is a transdermal agent.
 7. The external skin ulcer treatment agentcomposition claimed in claim 1, wherein R² in formula (I) is a pentylgroup, and the external skin treatment agent in formula (I) is atransdermal agent.
 8. The external skin ulcer treatment agentcomposition claimed in claim 1, wherein R¹ in formula (I) is a hydrogenatom or a methyl group, and R² in formula (I) is a pentyl group, and theexternal skin treatment agent in formula (I) is a transdermal agent. 9.The external skin ulcer treatment agent composition claimed in claim 1,wherein the external skin treatment agent is an agent for treatment ofulcers wherein said ulcers are selected from the group consisting ofdecubitus ulcers, scald ulcers, angiopathic ulcers, diabetic ulcers,peripheral circulatory disorders and ulcers accompanying collagendiseases.
 10. The external skin ulcer treatment agent compositionclaimed in claim 1, wherein R¹ in formula (I) is a hydrogen atom or amethyl group, and the external skin treatment agent is an agent fortreatment of ulcers wherein said ulcers are selected from the groupconsisting of decubitus ulcers, scald ulcers, angiopathic ulcers,diabetic ulcers, peripheral circulatory disorders and ulcersaccompanying collagen diseases.
 11. The external skin ulcer treatmentagent composition claimed in claim 1, wherein R² in formula (I) is apentyl group, and the external skin treatment agent is an agent fortreatment of ulcers wherein said ulcers are selected from the groupconsisting of decubitus ulcers, scald ulcers, angiopathic ulcers,diabetic ulcers, peripheral circulatory disorders and ulcersaccompanying collagen diseases.
 12. The external skin ulcer treatmentagent composition claimed in claim 1, wherein R¹ in formula (I) is ahydrogen atom or a methyl group, R² in formula (I) is a pentyl group,and the external skin treatment agent is an agent for treatment ofulcers wherein said ulcers are selected from the group consisting ofdecubitus ulcers, scald ulcers, angiopathic ulcers, diabetic ulcers,peripheral circulatory disorders and ulcers accompanying collagendiseases.
 13. The external skin ulcer treatment agent compositionclaimed in claim 1, wherein the external skin treatment agent in formula(I) is a transdermal agent and is an agent for treatment of ulcerswherein said ulcers are selected from the group consisting of decubitusulcers, scald ulcers, angiopathic ulcers, diabetic ulcers, peripheralcirculatory disorders and ulcers accompanying collagen diseases.
 14. Theexternal skin ulcer treatment agent composition claimed in claim 1,wherein R¹ in formula (I) is a hydrogen atom or a methyl group, and theexternal skin treatment agent in formula (I) is a transdermal agent andis an agent for treatment of ulcers wherein said ulcers are selectedfrom the group consisting of decubitus ulcers, scald ulcers, angiopathiculcers, diabetic ulcers, peripheral circulatory disorders and ulcersaccompanying collagen diseases.
 15. The external skin ulcer treatmentagent composition claimed in claim 1, wherein R² in formula (I) is apentyl group, and the external skin treatment agent in formula (I) is atransdermal agent and is an agent for treatment of ulcers wherein saidulcers are selected from the group consisting of decubitus ulcers, scaldulcers, angiopathic ulcers, diabetic ulcers, peripheral circulatorydisorders and ulcers accompanying collagen diseases.
 16. The externalskin ulcer treatment agent composition claimed in claim 1, wherein R¹ informula (I) is a hydrogen atom or a methyl group, and R² in formula (I)is a pentyl group, and the external skin treatment agent in formula (I)is a transdermal agent and is an agent for treatment of ulcers whereinsaid ulcers are selected from the group consisting of decubitus ulcers,scald ulcers, angiopathic ulcers, diabetic ulcers, peripheralcirculatory disorders and ulcers accompanying collagen diseases.
 17. Theexternal skin ulcer treatment agent composition claimed in claim 1,comprising 10⁻⁶ to 10⁻¹ % by weight of the active ingredient.
 18. Theexternal skin ulcer treatment agent composition claimed in claim 1,comprising 10⁻⁵ to 10⁻² % by weight of the active ingredient.
 19. Amethod of treating external skin ulcers comprising administering to apatient in need of such treatment an anti-external skin ulcer effectiveamount of a pharmaceutical composition comprising an active ingredientwherein the active ingredient comprises a prostacyclin, and/or itsoptical isomer, having the formula (I): ##STR8## (wherein R¹ is ahydrogen atom, a straight chain or branched alkyl group of C₁ to C₁₀, orone equivalent of cations, R² is (CH₂)R²¹ or a substitutable C₃ to C₁₀cycloalkyl group, where R²¹ is a substitute C₁ to C₁₀ straight chain orbranched alkyl group or substitutable C₂ to C₁₀ straight chain orbranched alkenyl group or alkynyl group, and R³ and R⁴ are independentlya hydroxyl group or formula: ##STR9## (wherein, R⁵ is a C₁ to C₅straight chain or branched alkyl group)) and a carrier.